C-reactive protein (CRP) is a prototypic acute phase protein in human and rabbit. Although it is structurally and functionally conserved from invertebrate to human, there are species-specific differences in patterns of expression and putative function. To further investigate the biological significance, regulation, and evolution of CRP, we isolated Xenopus CRP and subsequently derived and sequenced corresponding cDNA and the genomic clones. The structure and expression of Xenopus CRP were also compared to those of the other CRPs. Analyses of the amino acid sequence and the nucleotide sequence reveal that the mature Xenopus CRP is a 222-amino acid protein preceded by a 16-residue signal peptide. During development, Xenopus CRP is expressed, only when the liver appears, and therefore is not likely to play a role in early embryonic development. Compared to other species, Xenopus CRP is present at an intermediate low level of < 1 microgram/ml in the normal serum. Unlike human and rabbit CRP, Xenopus CRP is not induced by turpentine or heatshock treatment. The heatshock consensus sequence (Woo, P., Korenberg, J. R., and Whitehead, A. S. (1985) J. Biol. Chem. 265, 4136-4142) are not present in the Xenopus CRP gene. It is suggested that Xenopus CRP represents a transitional period in CRP evolution when host defenses switched from primitive innate immunity to a much more complex immune system. The constitutive functions of CRP gradually became less essential as the result of the development of a complex immune system.